Breast cancer is the most common non-cutaneous malignancy in women. It is estimated that there were 212,600 new cases in 2003 in the USA. It is estimated that at least 13% of women will develop breast cancer at some time in their life, and this incidence is increasing. As more than 80% of breast tumors grow in response to sex hormone stimulation caused by estrogen, part of adjuvant therapy (i.e. therapy in addition to surgical removal of the tumor) is to administer an agent to block this growth stimulation, including by means of blocking estrogen receptor activation or blocking estrogen production.
One such agent has been tamoxifen. Notwithstanding its success in adjuvant breast cancer therapy, tamoxifen has unwanted side-effects, which can be categorized into estrogen receptor stimulating (uterine cancer, deep venous thrombosis) and estrogen receptor antagonizing (vaginal dryness, hot flushes, mood swings) and has led to the search for a better alternative. A more selective estrogen receptor regulator has so far not been successful in taking the place of tamoxifen and the current trend in hormonal therapy is to reduce the level of bio-available estrogen.
Another such agent has been aminoglutethimide (Cash, Brough et at 1967). This drug was poorly tolerated and resulted in a marked adrenal suppression that limited the use of the drug.
Over the past 15 years, however, more specific enzyme inhibitors have been developed, which specifically inhibit the aromatase enzyme that converts testosterone to estradiol. These compounds are known as aromatase inhibitors. They are used to block the conversion of testosterone to estradiol, resulting in non-tissue-specific enzymatic inhibition and almost complete ablation of testosterone conversion to estradiol. The relevant conversion pathways are shown in FIG. 1.
The development of these aromatase inhibitors, such as exemestane (Aromasin®), anastrozole (Arimidex®) and letrozole (Femara®) has brought about a major change in the therapeutic approach to patients with hormone-sensitive breast cancer. In randomized clinical trials, each of these aromatase inhibitors has demonstrated efficacy in the adjuvant treatment of post-menopausal women with receptor-positive tumors. Although long-term follow up for safety and overall survival continues in each of these trials, currently available data suggest that an aromatase inhibitor should now be included as part of adjuvant endocrine therapy for the great majority of receptor-positive post-menopausal patients. The current strategy comprises at least five years of global estrogen deprivation with a tissue non-specific aromatase inhibitor. These aromatase inhibitors overcome the significant adrenal toxicity of the previous anti-estrogen medications, and this has allowed them to now become the most widely prescribed hormonal therapy for breast cancer.
A significant problem with these aromatase inhibitors, however, is that they cause unwanted and substantial short and long-term side effects. Examples of these side effects include, but are not limited to, vasodilatation, osteoporosis, osteopenia, loss of libido, weight gain, vaginal dryness, sleeping difficulties, night sweats, asthenia, painful intercourse, pain, arthritis, arthralgia, breast pain, pharyngitis, depression, bloating, nausea, rash, mood swings, headache, diminished cognitive function, hypertension, insomnia, lymphoedema, back pain, peripheral edema, cold sweats, abdominal pain, injury, constipation, coughing, diarrhea, fracture, hypercholesteremia, infection, arthrosis, dizziness, dyspnea, paraesthesia, urinary tract infection, vulvovaginitis, anxiety, bone pain, chest pain, dyspepsia, flu syndrome, gastrointestinal disorder, sweating and/or leukorrhea.
The present invention described herein differs from other hormonal therapy methods for the treatment of breast cancer. It provides the advantages of androgen replacement therapy in combination with an aromatase inhibitor.
Current therapeutic circumstances in which an aromatase inhibitor (e.g., Arimidex®) and an androgenic agent (e.g., testosterone) have been used in combination previously are to reduce the estrogenic effect of testosterone abuse in body building, in particular gynaecomastia (Hoffmann J Raatamess N Journal of Sports Science and Medicine 5, 182-183 (2006), to reduce estrogenic side-effects in hypogonadal men on T therapy (Leder et al. 2004, and Leder et al. 2005), and to explore the safety issues (risk of cardiovascular disease) of androgen replacement therapy, specifically in female to male transexuals undergoing testosterone therapy. (Bunck at al. 2006). None of these circumstances of androgen replacement therapy, however, were for the treatment of a woman diagnosed with breast cancer. In fact, there has been a great reluctance by the medical profession to prescribe hormone substrates to women who have hormonally active breast cancers. The use of androgen replacement is controversial in post-menopausal women generally, and its use in women who have had breast cancer is almost universally contra-indicated. For example, a Proctor & Gamble application to the FDA for the Intrinsa product cited breast cancer as an absolute contra-indication to using the Intrinsa patch because of the concern about the testosterone being converted to estradiol and being used as a growth substrate by the malignancy (Shifren J L et al Testosterone patch for the treatment of hypoactive sexual desire disorder in naturally menopausal women: results from the INTIMATE NM1 study Menopause (in press).
Regardless of such medication, the conventional understanding remains that androgen (e.g., testosterone) replacement should be avoided in breast cancer subjects for fear of spurring tumor regrowth.
The present invention, however, goes against this conventional wisdom of not prescribing androgenic agents to women diagnosed with breast cancer. The present invention provides a novel therapy to alleviate side-effects of and/or to enhance the efficacy of aromatase inhibitor therapy in breast cancer treatment by supplementing and/or combining an aromatase inhibitor with an androgenic agent.